The clotting cascade is triggered when the plasma protease, factor VIIa, binds to the integral membrane protein, tissue factor, on cell surfaces. The resulting two-subunit enzyme activities factors IX and X by limited proteolysis. The long-term goal of this project is to understand the role of the tissue factor/factor VIIa complex in thrombotic disease, with emphasis on understanding the role of plasma factor VIIa levels and tissue factor gene polymorphisms in hypercoagulable states, and how phospholipid compositions and anti-phospholipid antibodies may alter factor VIIa/tissue factor function. Specifically, the project will address the following questions: (1) Are elevated plasma levels of factor VIIa or factor VIIa-anti-thrombin complexes risk factors for thrombotic disease? (2) Are polymorphisms in the tissue factor gene associated with risk of thrombotic disease? (3) How do phospholipid-Gla domain interactions affect factor VIIa activity? How do anti-phospholipid antibodies and lipid oxidation alter the activity of tissue factor? Achieving the goals of this project will provide basic knowledge about how the triggering phase of the blood clotting system is regulated. It will also provide insights into the role of plasma factor VIIa as a risk factor for thrombotic disease.